Kaposi' s sarcoma (KS), caused by the KS herpesvirus (KSHV) is an AIDS-associated malignancy (AIDS-KS) and is the most important malignancy of the oral cavity in HIV infected individuals. KS can be treated with local therapy, anti-retroviral therapy and chemotherapy; however, it is estimated more than a half of KS patients will not be cured. KS is characterized by the proliferation of spindle cells and deregulated angiogenesis caused by KSHV genes. The limited success of targeted pathogenesis-based therapies in AIDS- KS such as the use of mTORC1 and PDGFR inhibitors indicate the urgent need to increase our understanding of the interplay of viral and host factors underpinning KS oncogenesis for development of targeted therapies; and more importantly, to inform current therapies. Using animal models of Rac1-dependent and of KSHV- dependent KS oncogenesis developed in our lab, we molecularly delineate an oncogenic paracrine axis connecting the expression of the KSHV oncogene vGCPR with secretion of the paracrine factors in order to define novel therapeutic targets. Novel studies carried out in an unbiased manner led us to: 1) Identify PDGFR- alpha (PGFRA) as the most potent oncogenic driver signaling cascade activated in KS pointing to PDGFRA as a target for anti-KS therapies 2) Identify PDGFRA+ mesenchymal stem cells (MSC) as potential KS oncogenic progenitors. We hypothesize that the prominent activation of PDGFRA and its driver role in the tumors is a consequence of the intrinsic ability of KSHV to target this pathway to increase infectivity, persistence and replication in PDGFRA+ target MSC. (AIM 1) Will study the role of PDGFRA in KSHV infection of PDGFRA+ MSC KS progenitors and oncogenesis: (AIM 2) Will Identify host viral interactions conducive to sustained activation of PDGFRA. (Aim 3) Will seek to use genetic and drug inhibition studies and NGS (RNASeq) to identify and targeting mechanisms of PDGFRA-mediated tumorigenesis in KSHV infected tumors. This work will: 1) Identify phenotypic characteristics of the KS progenitor and how the biology of KSHV in these cells leads to oncogenesis 2) Identify key pathogenic mechanisms and new therapeutic approaches 3) Understand the interplay between PDGFRA and KSHV biology in KS tumors and how it affects pathogenesis and response to therapy